CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer

Justin H. Hwang; Ji Heui Seo; Michael L. Beshiri; Stephanie Wankowicz; David Liu; Alexander Cheung; Ji Li; Xintao Qiu; Andrew L. Hong; Ginevra Botta; Lior Golumb; Camden Richter; Jonathan So; Gabriel J. Sandoval; Andrew O. Giacomelli; Seav Huong Ly; Celine Han; Chao Dai; Hubert Pakula; Anjali Sheahan; Federica Piccioni; Ole Gjoerup; Massimo Loda; Adam G. Sowalsky; Leigh Ellis; Henry Long; David E. Root; Kathleen Kelly; Eliezer M. Van Allen; Matthew L. Freedman; Atish D. Choudhury; William C. Hahn

doi:10.1016/j.celrep.2019.10.068

CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer

Justin H. Hwang
, Ji Heui Seo
, Michael L. Beshiri
, Stephanie Wankowicz
, David Liu
, Alexander Cheung
, Ji Li
, Xintao Qiu
, Andrew L. Hong
, Ginevra Botta
, Lior Golumb
, Camden Richter
, Jonathan So
, Gabriel J. Sandoval
, Andrew O. Giacomelli
, Seav Huong Ly
, Celine Han
, Chao Dai
, Hubert Pakula
, Anjali Sheahan

Federica Piccioni, Ole Gjoerup, Massimo Loda, Adam G. Sowalsky, Leigh Ellis, Henry Long, David E. Root, Kathleen Kelly, Eliezer M. Van Allen, Matthew L. Freedman, Atish D. Choudhury, William C. Hahn^*

^*Corresponding author for this work

Surgery

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers.

Original language	English
Pages (from-to)	2355-2370.e6
Journal	Cell Reports
Volume	29
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2019.10.068
State	Published - 19 Nov 2019

Keywords

androgen deprivation therapy
androgen receptor
CREB5
metastatic castration-resistant prostate cancer
ORF screen
therapy resistance

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10.1016/j.celrep.2019.10.068

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Hwang, J. H., Seo, J. H., Beshiri, M. L., Wankowicz, S., Liu, D., Cheung, A., Li, J., Qiu, X., Hong, A. L., Botta, G., Golumb, L., Richter, C., So, J., Sandoval, G. J., Giacomelli, A. O., Ly, S. H., Han, C., Dai, C., Pakula, H., ... Hahn, W. C. (2019). CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer. Cell Reports, 29(8), 2355-2370.e6. https://doi.org/10.1016/j.celrep.2019.10.068

@article{04dfca39e5bd4b6d9d32d8b4e714ff90,

title = "CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer",

abstract = "Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers.",

keywords = "androgen deprivation therapy, androgen receptor, CREB5, metastatic castration-resistant prostate cancer, ORF screen, therapy resistance",

author = "Hwang, \{Justin H.\} and Seo, \{Ji Heui\} and Beshiri, \{Michael L.\} and Stephanie Wankowicz and David Liu and Alexander Cheung and Ji Li and Xintao Qiu and Hong, \{Andrew L.\} and Ginevra Botta and Lior Golumb and Camden Richter and Jonathan So and Sandoval, \{Gabriel J.\} and Giacomelli, \{Andrew O.\} and Ly, \{Seav Huong\} and Celine Han and Chao Dai and Hubert Pakula and Anjali Sheahan and Federica Piccioni and Ole Gjoerup and Massimo Loda and Sowalsky, \{Adam G.\} and Leigh Ellis and Henry Long and Root, \{David E.\} and Kathleen Kelly and \{Van Allen\}, \{Eliezer M.\} and Freedman, \{Matthew L.\} and Choudhury, \{Atish D.\} and Hahn, \{William C.\}",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = nov,

day = "19",

doi = "10.1016/j.celrep.2019.10.068",

language = "English",

volume = "29",

pages = "2355--2370.e6",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier B.V.",

number = "8",

}

Hwang, JH, Seo, JH, Beshiri, ML, Wankowicz, S, Liu, D, Cheung, A, Li, J, Qiu, X, Hong, AL, Botta, G, Golumb, L, Richter, C, So, J, Sandoval, GJ, Giacomelli, AO, Ly, SH, Han, C, Dai, C, Pakula, H, Sheahan, A, Piccioni, F, Gjoerup, O, Loda, M, Sowalsky, AG, Ellis, L, Long, H, Root, DE, Kelly, K, Van Allen, EM, Freedman, ML, Choudhury, AD & Hahn, WC 2019, 'CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer', Cell Reports, vol. 29, no. 8, pp. 2355-2370.e6. https://doi.org/10.1016/j.celrep.2019.10.068

TY - JOUR

T1 - CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer

AU - Hwang, Justin H.

AU - Seo, Ji Heui

AU - Beshiri, Michael L.

AU - Wankowicz, Stephanie

AU - Liu, David

AU - Cheung, Alexander

AU - Li, Ji

AU - Qiu, Xintao

AU - Hong, Andrew L.

AU - Botta, Ginevra

AU - Golumb, Lior

AU - Richter, Camden

AU - So, Jonathan

AU - Sandoval, Gabriel J.

AU - Giacomelli, Andrew O.

AU - Ly, Seav Huong

AU - Han, Celine

AU - Dai, Chao

AU - Pakula, Hubert

AU - Sheahan, Anjali

AU - Piccioni, Federica

AU - Gjoerup, Ole

AU - Loda, Massimo

AU - Sowalsky, Adam G.

AU - Ellis, Leigh

AU - Long, Henry

AU - Root, David E.

AU - Kelly, Kathleen

AU - Van Allen, Eliezer M.

AU - Freedman, Matthew L.

AU - Choudhury, Atish D.

AU - Hahn, William C.

PY - 2019/11/19

Y1 - 2019/11/19

N2 - Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers.

AB - Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers.

KW - androgen deprivation therapy

KW - androgen receptor

KW - CREB5

KW - metastatic castration-resistant prostate cancer

KW - ORF screen

KW - therapy resistance

UR - https://www.scopus.com/pages/publications/85075126229

U2 - 10.1016/j.celrep.2019.10.068

DO - 10.1016/j.celrep.2019.10.068

M3 - Article

C2 - 31747605

AN - SCOPUS:85075126229

SN - 2211-1247

VL - 29

SP - 2355-2370.e6

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer

Abstract

Keywords

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